Project Summary/Abstract Neural and behavioral systems have evolved to invigorate responding during specific life challenges. However, the neural and behavioral systems in place to cope with threats can be challenged by traumatic events, in worst cases leading to fear and anxiety disorders. The proposed research pursues the working hypothesis that the hypothalamic orexin (hypocretin) system is essential for active coping responses to threat. Orexin neurons, found exclusively in the perifornical and lateral hypothalamus, are activated by hunger, painful stimuli and by cues associated with these states and trigger an integrated organismal response to satisfy or escape them1,16,21-23,34,36,37. This includes endocrine and arousal-related functions 29,38-4218,30,43-46, and the invigoration of active (instrumental) behaviors1,47,48. Studies on the orexin system?s role in Pavlovian fear conditioning have yielded inconsistent results. Although ample research supports the orexin system?s importance in active, instrumental responses for reinforcers (i.e. food and drugs of abuse), the same cannot be said for aversively-motivated instrumental behaviors. Supported by preliminary data, the proposed research uses a signaled active avoidance paradigm (SigAA) to investigate when and how the orexin system is required for avoiding a learned aversive outcome. To accomplish this, pharmacology and optogenetics will be used to manipulate orexin-sensitive brain regions important for aversively-motivated behaviors, namely the central nucleus of the amygdala (CeA) and the ventral tegmental area (VTA). Specific Aim 1 will test the prediction that orexin activity in CeA is required for active avoidance through suppressing passive reactions (freezing) to learned threatening stimuli (the conditioned stimulus (CS), a tone that has been paired with a mild footshock). Specific Aim 2 will focus on the dopaminergic VTA, a region required for active instrumental behaviors, with the hypothesis that orexin activation of this brain nucleus is required to initiate avoidance. Both aims will use brain -region specific optogenetic manipulations to establish these circuits in SigAA and to test the prediction that orexin activity occurs specifically during the CS. Subsequent studies will use pharmacological manipulations to test the hypothesis that avoidance responses are mediated by orexin-1 receptor activity. Together, these studies aim to change how the field views the orexin system, from a modulator of (mainly) appetitive motivation, to a general mediator of instrumental response selection, regardless of the valence of the outcome. These studies will also challenge the dominant methodological paradigm (fear conditioning), with the potential to reveal the nature of the orexin system in both the appetitive and aversive learning realms. Successful completion of these studies will uncover the orexin system?s role in adaptive coping behaviors and provide evidence-based support for novel treatments of maladaptive coping, including active coping therapy combined with drugs to target the orexin system.